Accepted Manuscript

Understanding symptoms and quality of life in patients with dry eye syndrome

Stefano Barabino, MD, PhD, Marc Labetoulle, MD, Maurizio Rolando, MD, Elisabeth
M. Messmer, MD
PII: S1542-0124(16)30039-8
DOI: 10.1016/j.jtos.2016.04.005
Reference: JTOS 183

To appear in: Ocular Surface

Received Date: 23 November 2015

Revised Date: 23 February 2016
Accepted Date: 14 April 2016

Please cite this article as: Barabino S, Labetoulle M, Rolando M, Messmer EM, Understanding
symptoms and quality of life in patients with dry eye syndrome, Ocular Surface (2016), doi: 10.1016/
j.jtos.2016.04.005.

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 ACCEPTED MANUSCRIPT

SECTION: Clinical Practice, Pedram Hamrah, MD, Editor

TITLE: Understanding symptoms and quality of life in patients with dry eye
syndrome

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AUTHORS: Stefano Barabino, MD, PhD,1 Marc Labetoulle, MD,2 Maurizio Rolando,
MD,1 and Elisabeth M. Messmer, MD3

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SHORT TITLE: SYMPTOMS AND QUALITY OF LIFE IN DED/Barabino et al

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FOOTNOTES

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Accepted for publication April 2016.
From 1Clinica Oculistica, DiNOGMI, Università di Genova, Genoa, Italy, 2Service
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d'Ophthalmologie, CHU Bicêtre, Université Paris Sud, Kremlin-Bicêtre, France, and
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Augenklinik der Ludwig-Maximilians-Universität, Munich, Germany.
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Sources of support: The roundtable meeting was sponsored and funded by Farmigea,
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Italy.
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Disclosures: The authors have no commercial or proprietary interest in any concept of

product discussed in this article.
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Single-copy reprint requests to Stefano Barabino, MD, PhD (address below).

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Corresponding author: Stefano Barabino, Clinica Oculistica, DiNOGMI, Università di

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Genova, viale Benedetto XV, 5, 16135 Genoa, Italy, email: sbarabi@tin.it

ABSTRACT Dry eye disease (DED) is one of the most common reasons for patients
(particularly those over the age of 50) to seek ophthalmic care. There is a wide array of
causes for DED that can induce an alteration of the ocular surface system and determine
the chronicity of the disease, including low blink rates (eg, computer use), systemic and

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topical drugs, autoimmune diseases, contact lens wear, and cataract and refractive
surgery. Patients with dry eye experience numerous symptoms that can reduce their
productivity and overall quality of life. This article presents the results of a roundtable
focused on patients’ symptoms. The goal was to better understand more exactly the
symptoms reported by patients, the possible effects on visual function, the consequences

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on the quality of life, and the methodologies that can be used to measure and monitor
symptoms in clinical practice and in clinical studies. The discrepancies between clinical

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signs and symptoms reported in some cases are considered in the context of the ocular
surface system.

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KEY WORDS dry eye disease, inflammation, ocular surface, quality of life,

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questionnaires, symptoms, therapy, visual function

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Outline
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I. Introduction
II. Symptoms of Dry Eye Disease
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III. Vision Changes in Dry Eye

A. Measurement of Visual Acuity
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B. Tear Film and Corneal Surface Analysis

C. Blink Rate and Aberrations
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IV. The Relationship between Symptoms and Ocular Surface Changes

V. Understanding Dry Eye Symptoms Following Cataract and Refractive Surgery
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VI. Measuring the Impact of Dry Eye Disease on Quality of Life

A. Questionnaires to Evaluate Symptoms
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B. Questionnaires to Specifically Assess Effect on Quality of Life

1. Medical Outcome Study Short Form-36
2. Time Trade-Off Method
3. National Eye Institute Visual Function Questionnaaire
4. Impact of Dry Eye on Everyday Life Questionnaire
5. Ocular Surface Disease QoL Questionnaire

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C. Comparison of Questionnaires
VII. Consequences of Decreased Quality of Life in Dry Eye Syndrome
VIII. Conclusions

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I. Introduction
Dry eye disease (DED) is one of the most common ocular complaints and reasons for

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patients to seek eye care.1 Schaumberg and colleagues conducted two large population
studies to measure the prevalence of dry eye in men and women.1,2 They found that the

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prevalence of DED in women increases with age from 5.7% among those <50 years of
age to 9.8% in those ≥75 years of age.2 Similarly, the prevalence of DED in men
increased from 3.9% in those 50-54 years of age to 7.7% in men ≥80 years of age.1

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There are numerous causes of dry eye, which are generally subdivided into the
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categories of aqueous-deficiency and evaporative.3 Several causative factors can
contribute to DED, such as topical and systemic drugs, lacrimal duct obstruction, and
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lacrimal deficiency. Cataract and refractive surgery can also induce dry eye syndrome or,
at least, dry eye-like symptoms.
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Symptoms comprise the main problem that drives patients to seek eye care. The
importance of symptoms has been highlighted by its inclusion in the definition of dry eye
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given in 1995 by the National Eye Institute and industry workshop,4 by the Japanese
study group in 2006,5 and by the International Dry Eye Workshop (DEWS)3 panel, which
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defined DED as “a multifactorial disease of the tears and ocular surface that results in
symptoms of discomfort, visual disturbance, and tear instability with potential damage to
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the ocular surface. It is accompanied by increased osmolarity of the tear film and
inflammation of the ocular surface.”
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Despite the importance of symptoms in dry eye, there are currently no gold standard
tests to classify them. Moreover, it is not uncommon for patients to have moderate-to-
severe symptoms in the absence of abnormal ocular surface signs, or for patients with
severe clinical signs to have relatively mild symptoms, due to the loss of sensitive
receptors into the cornea. These discrepancies underscore the need to better understand
symptoms analysis and ocular surface signs.

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In April 2015, a group comprised of four dry eye specialists met in Milan, Italy, for a
2-day roundtable meeting whose purpose was to consider the scale of the problem of
symptoms of dry eye, including changes in visual function, the tests currently available to
measure these changes, and the relationship between symptoms reported by patients and
ocular surface changes. The meeting was sponsored and funded by Farmigea, Italy.

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II. Symptoms of Dry Eye Disease

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When a patient presents with any of the complaints reported in Table 1, DED
should be suspected.3,6,7 It is important discover the frequency, duration, and triggering

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factors for the dry eye symptoms. A full medical history should be obtained.8 The
behavior of ocular surface symptoms during the day is different in DED, allergy, and
blepharitis, and this can be of help in diagnosis (Figure 1).9 The history may uncover

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contributing factors, such as medications, smoking, menopause, or some underlying
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systemic disease (Table 2). Although open dialogue with the patient is important, the
information obtained from patient perceptions is generally qualitative. Moreover, there
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may be considerable variation between visits, patients, and physicians’ perceptions.
Patient questionnaires and objective tests can provide additional information to help
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manage these diagnostic challenges.

Questionnaires provide consistent information and are excellent tools for both
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clinical research in DED and clinical practice. These instruments can explore many
aspects of the disease, including the burden of DED and its effect on a patient’s quality of
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life (QoL). A number of questionnaires have been developed to identify dry eye
symptoms and to assess levels of severity. The steps for building and validating a
questionnaire are summarized in Table 3.10,11 In some cases questionnaires for DED have
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not been developed specifically for DED. The SF-3612 and the National Eye Institute
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Visual Functioning Questionnaire (NEI-VFQ)13-15 are examples of questionnaires used in

other disease states and applied to DED. Questionaires used to assess DED symptoms are
discussed in Section IV.A.

III. Vision Changes in Dry Eye Disease

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In 1995, the definition of DED focused simply on symptoms, interpalpebral surface

damage, and tear instability.4 Symptoms were related to a generic “ocular discomfort.”
The definition formulated by the 2007 DEWS panel includes symptoms of discomfort but
has added visual disturbances as an additional factor.9 Patients with DED often complain
of reduced visual function,16 manifesting as glare and blurred or fogged vision.12,17,18

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A. Measurement of Visual Acuity

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Snellen or logMAR charts (e.g., the Early Treatment Diabetic Retinopathy Study
[ETDRS] chart) are typically used to measure visual acuity (VA).16 The ETDRS charts

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were designed as an improvement to the Snellen charts and have become the standard for
use in clinical trials.16,19 Because the reduction in VA experienced by DED patients is

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usually transitory and can be overcome by increased blinking, differences in visual
function between patients with DED and those without the disease may be difficult to
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discern by ETDRS charts or by other recently developed VA charts (e.g.,
MNREAD).16,20,21
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Functional VA can be measured in DED patients with methods such as spatial-
contrast sensitivity.22-26 Rolando et al found that spatial-contrast sensitivity was 35% to
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70% lower in patients with DED than in a group of age-matched normals22 and is
reduced both in the presence and absence of glare for those suffering from DED.24
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Contrast sensitivity has been shown to improve in dry eyes after the administration of
artificial tears.23,25 Functional VA can be studied also in terms of reading speed. Ridder
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and colleagues demonstrated that reading performance decreases with increasing severity
of dry eye, and this factor might even be used to monitor the improvement with treatment
in patients with DED.26
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A specific simulator was used in a prospective case-control study to assess the driving
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visual performance in patients with DED and to determine clinical predictors of visual
impairment while driving.27 The driving simulator displayed randomly located targets
with progressive increases in contrast. Clinical examinations, serial measurements of
corneal higher-order aberrations (HOAs), and evaluation with OSDI questionnaires were
conducted. The percentage of targets missed and the average response time were
significantly increased in patients with DED compared with controls. Dry eye patients

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demonstrated a positive correlation between the response time and the progression index
for HOAs and with the OSDI symptoms subscale.

B. Tear Film and Corneal Surface Analysis

Changes in visual function can be measured indirectly by assessing the stability of the

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tear film, e.g., the tear film break-up time (TFBUT),8 or by studying the corneal surface.
TFBUT can be analyzed by corneal topography and the ratio of breakup area in an entire

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color-coded area can be calculated, providing a noninvasive objective measure of tear
film stability.28 One study showed the sensitivities for these two tests was 97.5% and

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95%, respectively. These values were significantly higher than the sensitivity of slit lamp
microscopy with fluorescence staining (75%).28
DED can affect corneal surface regularity.29 A tear analysis system has been used to

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compare the surface regularity index (SRI), surface asymmetry index (SAI), potential
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visual acuity (PVA) index, and topographic pattern between normal and dry eyes and in
dry eyes before and after the instillation of artificial tears.29 The SRI and SAI were
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significantly elevated in patients with DED compared with normal subjects. Interestingly,
the average degree of astigmatism was also higher in dry eyes (2.10+/-1.96 prism
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diopters) compared with normal eyes (1.13+/-0.53 prism diopters). The SRI and SAI
were positively correlated with corneal fluorescein staining scores in dry eyes. Following
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the administration of artificial tears, the SRI, SAI, and mean astigmatism decreased
significantly and the PVA improved in dry eyes. This tear analysis system appears to
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have utility in the diagnosis of dry eye and assessment of treatment efficacy.30
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C. Blink Rate and Aberrations

Goto and colleagues found that functional VA was reduced significantly, from 1.18 to
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0.336 in non-SS patients and from 1.15 to 0.228 in SS patients, after they gazed for 10-20
seconds without blinking.31 In addition, blinking rate during reading and driving were
significantly reduced. Another study used a continuous functional VA measurement
system to evaluate monocular recognition acuity during a 30-second period of no
blinking.32 FVA in patients with dry eye was significantly lower than those of control
subjects at all time points.

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Kaido et al studied changes in functional VA and higher order aberrations in patients

with DED.33 Eyes were subdivided into those with or without superficial punctate
keratopathy (SPK) in the central cornea of 22 patients with Sjögren syndrome. Eyes of
10 normal subjects served as the controls. Serial assessments of VA higher order
aberrations were performed under blink-free conditions (without topical anesthesia) over

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a 10-second period. The visual maintenance ratio (VMR) was the ratio of functional VA
divided by the baseline. Dry eye patients with SPK experienced significant deteriorations

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of visual function and optical quality compared with dry eye patients without SPK and
normals, as measured by the VMR, the variation of VA, and by coma-like and total

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higher order aberrations. These results support the hypothesis that optical disturbances
from DED in the central portion of the cornea affect FVP. The progressive degradation of

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ocular optical quality has been shown to result from the loss of contrast at intermediate
and high spatial frequencies in DED patients.34 The same study found that the
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progression index for corneal HOAs was correlated with objective clinical findings of
tear film and ocular surface damage and the subjective index of patient-reported visual
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outcomes.
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IV. The Relationship between Symptoms and Ocular Surface Changes

The components of the Ocular Surface System (OSS) are functionally linked by
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the continuity of the surface epithelium,3 and all of the components of the OSS must
function normally to preserve optimal visual function.35-37 Protective mechanisms of the
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ocular surface epithelium include its ability to heal rapidly and adhere to the underlying
connective tissue.3 This is critical, since the cornea and ocular surface are exposed to the
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external environment. Moreover, blinking and rubbing of the eye put mechanical stress
on the epithelium. The corneal epithelium turns over about every 5-7 days.38,39
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The tight junction, or zonula occludens (ZO), forms a semipermeable barrier in the
paracellular pathway in the epithelia.40,41 The ZO is the apical-most component of a series
of intercellular junctions, known as the junctional complex, on the interface of the apical
and lateral cell surface. This structure not only restricts movement of substances around
the cells, but also acts to maintain the cell surface compositional polarity characteristic of
epithelial cells. Adherence junctions occur between epithelial cells and involve cadherins

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and catenins.40,41 Both the tight and adherence junctions are closely linked to the actin
cytoskeleton.
The barrier function of the corneal epithelial layer can be disrupted in DED and
induce symptoms of discomfort and visual disturbances. As noted in Section I, symptoms
are not always associated with clinical signs in patients with DED.42,43 Patients with

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severe fluorescein staining may not report severe symptoms, while patients with low or
no staining may suffer of numerous symptoms. The lack of direct correlation between

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symptoms and corneal staining might be explained by the relationship between changes
of corneal nerves, osmolarity, and inflammation.

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Osmolarity plays an important role in the pathogenesis of the ocular surface
damage44-46 and symptoms of dry eye.47Although the molecular mechanisms involved in

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sensing high osmolarity in the extracellular environment are not well defined in humans,
one study demonstrated that yeast Msb2 and Hkr1, which are related to mammalian
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mucins, are viable candidates for sensing osmotic stress and/or activating compensatory
mechanisms involved in osmostress adaptation.48 Transmembrane mucins activate
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several signaling cascades in mammals and could therefore be important for sensing
osmotic imbalances in higher eukaryotes. Increased osmolarity associated with DED can
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have a variety of deleterious effects on the ocular surface. Cellular processes such as
metabolism, protein folding, intracellular transport require stable osmolarity/tonicity.49
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Responses of epithelial cells exposed to hyperosmolarity include reduced cell volume,

increased concentration of solutes, oxidative stress, disruption of DNA repair systems
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and therefore DNA damage, and increased pro-apoptotic signaling.49 Corneal epithelial
cells exposed to hyperosmotic conditions have demonstrated reduced intercellular
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connections, loss of cell surface microplicae and desmosomes, disruption of cell

membranes, epithelial desquamation, and mucous threads.50
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Hyperosmolarity potentiates the toxic effects of benzalkonium chloride (BAK) -–

the most commonly used preservative in eye drops-- on conjunctival epithelial cells.51
This occurs through the induction of oxidative stress, reduction of cell viability, increases
in cell membrane permeability, cell shrinkage with cell blebbing, and chromatin
condensation. Hyperosmotic stress also increases cell death in a concentration-dependent
manner via a caspase-dependent apoptosis. BAK disturbs the tear film and may promote

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hyperosmolarity, thus enhancing its own cytotoxicity. Symptoms of discomfort could

therefore be exacerbated by chronic treatment with BAK-containing substitute tears, and
this should be considered when prescribing a chronic treatment to patients.
The hyperosmolarity associated with DED stimulates a cascade of inflammatory
events. Luo and colleagues found that hyperosmolarity associated with experimental dry

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eye stimulates the expression and production of matrix metalloproteinase-9 (MMP-9),
IL-1-β, and TNF-ɑ.52 These conditions also activate JNK, ERK, and p38 mitogen-

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activated protein kinase (MAPK) signaling pathways on the ocular surface.53-55 MAPKs
stimulate the production of inflammatory cytokines and MMPs, and they could play an

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important role in the induction of these factors, which may play a role in the pathogenesis
of dry eye disease. According to Rolando et al, tears containing pro-inflammatory
cytokines could be considered “toxic tears,”56 and could be responsible for symptoms

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reported by patients in the earliest phases of the disease; at this stage, the eyes are still
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wet and show almost no sign of ocular surface damage, but the conjunctival epithelium
has higher than normal expression of markers of inflammation such as HLA-DR.
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The activation of the immune system of the ocular surface in dry eye is even more
complex and has been extensively described by Barabino et al.57 The exact relationship
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between symptoms and inflammation/activation of the immune system has not been
elucidated thus far. However, it is certainly clear that anti-inflammatory treatment can
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decrease symptoms of dry eye, as described below.

Decreased corneal sensation is another possible reason for the paradoxical finding of
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minimal symptoms of discomfort in the presence of severe ocular surface damage. The
corneal epithelial layer has a high density of nociceptors that has been estimated to be 20-
40-fold greater than in the dental pulp and 300 to 600 times that of the skin.58 These
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nerve terminals are located between the cells of the epithelium, where they often reach
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the border between surface epithelial cells.59,60 The nociceptors under normal conditions
are protected from the outside environment by the glycocalyx, mucin layer, and tear film.
In DED, the lack of this protection determines the release of neuropeptides (substance P
and calcitonin gene-related peptide) that promote an inflammatory reaction (neurogenic
inflammation).61 Hyperalgesia in early or mild DED cases is probably due to this
mechanism. Conversely, decreased symptoms in cases of severe disease are thought to be

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due to downregulation of sensory receptors. It has been demonstrated that in these cases
there is a local decrease of sensitization. A decrease in the number and density of
subbasal nerves has been observed in patients with dry eye.62,63 There are also some
changes at the level of the central nervous system that could explain the anxiety and
depression signs that we elucidated before.

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VI. Understanding Dry Eye Symptoms Following Cataract and Refractive

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Surgery
Several factors may contribute to the development of dry eye symptoms following

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cataract surgery, including microscope light, povidone-iodine, corneal incision, lid
speculum, and inflammation. Barabino et al evaluated the symptoms of dry eye and signs
of ocular surface damage in 40 normal patients following cataract surgery.64 Statistically

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significant changes compared to baseline were found in symptoms, corneal fluorescein
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staining, lissamine green conjunctival staining, TFBUT, and the Dynamic Lipid
Interference Pattern (DLIP) test at days 1 and 7. At day 30, the changes were still
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significant for TFBUT (Figure 2) and DLIP, and at day 60 for DLIP only. Interestingly,
the Schirmer I test did not show any significant changes during the study. Similar results
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were obtained by other authors,65,66 and changes in mean goblet cell density 3 months
postoperatively have also been demonstrated.67 These results suggest that cataract surgery
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may induce a clinical response that is similar to dry eye.

As with chronic DED, dry eye that occurs after cataract surgery is responsive to
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treatment. One study showed that adding an artificial tears to the regular postoperative
cataract surgery therapeutic regimen improved TFBUT, OSDI scores, ocular symptoms
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subscale scores, vision-related function subscale score, and inflammatory markers (CD3
and HLA-DR via impression cytology).68
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Dry eye can also occur after refractive surgery.69-71 Most patients experience
symptoms of tear dysfunction after laser in situ keratomileusis (LASIK) and
photorefractive keratectomy (PRK).69,70 Complaints of dry eye are a leading source of
patient discomfort and dissatisfaction after LASIK. However, the symptoms are not
uniform, and the disease is multifactorial. Post-LASIK tear dysfunction syndrome or dry
eye is a term that describes a spectrum of disease encompassing transient or persistent

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postoperative neurotrophic disease, aqueous tear deficiency, tear-film instability, and

neuropathic pain. Fortunately, most cases of postoperative dry eye symptoms resolve
with appropriate management. This involves taking steps to optimize ocular surface
health before and after surgery. Although it is not clear whether surgical procedures
induce the “traditional” dry eye syndrome, we can state that they certainly provoke dry

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eye-like symptoms, which negatively influence the patients’ perception of surgical
success. It is therefore important to study the ocular surface conditions before cataract

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and refractive surgery to prevent complications by treating eventual alterations of the
system. In managing postoperative follow-up, we should pay attention to tear film, ocular

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surface epithelia, and meibomian glands and treat any abnormalities.

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IV. Measuring the Impact of Dry Eye Disease on Quality of Life
Symptoms and changes in visual function cause a significant decrease of the QoL
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of patients with DED. Although questioning patients can yield useful information with
regard to the effect of DED on their QoL, reliable assessment parameters would be highly
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valuable for monitoring QoL changes over time and evaluating the effect of treatment in
clinical practice and clinical studies. Most questionnaires to evaluate symptoms also
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address their effect on QoL. Other questionnaires are specifically directed to evaluating
the effects of DED on QoL, and some of these are adapted from questionnaires related to
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other diseases.
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A. Questionnaires to Evaluate Symptoms

The principal characteristics of several questionnaires that have been developed
for use specifically in DED are summarized in Table 4.2,12,13,17,72-82 The Ocular Surface
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Disease Index (OSDI) is a 12-item questionnaire (graded on a scale from 0 to 4) that

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assesses the symptoms of ocular irritation associated with dry eye disease and their
impact on visual function.72 The McMonnies questionnaire combines several types of
questions.83,84 It is a screening survey for patients but it is not well suited for clinical
research. The Canadian Dry Eye Epidemiologic Study (CANDEES) questionnaire is
designed for epidemiological studies,81,85 but it is not well suited for clinical assessments.
The Dry Eye Questionnaire (DEQ) contains 23 main questions (68 questions overall).7,86

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It captures: age, gender, contact lenses (type, reasons for withdrawal), subjective signs
(time, frequency, intensity, and impact), frequency of objective data (e.g., redness, watery
eyes), computer use, and ocular and systemic medications.
A 12-item Ocular Comfort Index (OCI) questionnaire measures ocular surface
irritation.87 The OCI has a positive correlation with OSDI scores and a negative

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correlation with TFBUT. The OCI is able to detect improvement in dry eye symptoms
after treatment. The instrument appears suitable for assessing changes in DED severity

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resulting from disease progression or therapy.
A panel of experts developed the Symptom Assessment iN Dry Eye (SANDE)

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questionnaire to quantify the frequency and severity of symptoms of dry eye syndrome
(DES) based on a visual analog scale (VAS).88 The questionnaire uses a 100 mm

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horizontal VAS technique to quantify patient ocular dryness and/or irritation symptoms.
Repeatability measures were consistently favorable for SANDE questionnaires
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administered within a few days of each another.
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B. Questionnaires to Specifically Assess Effect on Quality of Life
1. Medical Outcome Study Short Form-36
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The Medical Outcome Study Short Form-36 (SF-36)89 is a 36-item questionnaire that
measures health status in the following areas: Physical Functioning, limitations caused by
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physical problems (Role-Physical), Bodily Pain, General Health Perceptions, Vitality,

Social Functioning, limitations caused by emotional problems (Role-Emotional), and
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Mental Health. Mertzanis and colleagues conducted a study using the SF-36 to compare
the burden of DED on daily life in normal patients versus those with non-Sjögren DED
and Sjögren DED.89 Individuals with moderate DED had significantly lower scores on
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Role-Physical, Bodily Pain, Vitality, Role-Emotional, and Mental Health compared with
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the normal control subjects. Those with severe disease had lower scores in all areas
except Role-Emotional and Mental Health compared with the normal control subjects.
These results highlight the adverse effects that DED can have on an individual’s daily
activities. The SF-8 is shorter, 8-item questionnaire that covers the same eight domains as
the full SF-36.90,91

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2. Time Trade-Off Method

The time trade-off method (TTO) evaluates the quality of life of a patient by having
the participant choosing to live a defined number of years in an impaired state of health
compared to living a shorter period of time in full health, essentially trading length of life
for QoL.92 Health-related QoL is expressed as a “utility.” Unfortunately, there is no

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consensus on the optimal specification for the TTO test. Using the TTO method, Nease et
al discovered that some forms of visual impairment imposed a greater QoL burden to the

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patient than symptoms of angina.93 Schiffman et al measured utility scores for dry eye
and compared them with other medical conditions.18 The comorbidity-adjusted utility

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score for moderate dry eye was comparable to that reported for moderate angina. Severe
dry eye and severe dry eye requiring tarsorrhaphy caused even greater reduction in utility.

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For comparison, monocular painful blindness produced a similar utility score. These
results highlight the degree of life burden that DED places on afflicted individuals.
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3. National Eye Institute Visual Function Questionnaaire
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The National Eye Institute Visual Function Questionnaire (NEI-VFQ) evaluates
patient impressions of their QoLas it relates to vision.14 Nichols et al used the 25-question
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NEI-VFQ to assess its repeatability and performance in 75 patients with dry eye.14 The
European criteria for dry eye were used to measure dry eye severity. Repeatability of
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individual NEI-VFQ-25 questions ranged from moderate (for pain and discomfort) to
substantial (stay home because of vision). Using the NEI-VFQ-25, dry eye patients had
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lower ocular pain subscale scores.

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4. Impact of Dry Eye on Everyday Life Questionnaire

The Impact of Dry Eye on Everyday Life (IDEEL) questionnaire94 is comprised of
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three modules with six scales QoL (Activity Limitations, Emotional Well-Being, and
Work Impact), Treatment Satisfaction (Treatment Satisfaction and Treatment-Bother),
and Symptom-Bother.12 Higher scores denote a better QoL (scale 0 to 100). This
instrument has a greater ability to differentiate levels of dry eye severity than generic
QoL questionnaires such as the SF-36 and EQ-5D.12,95 The IDEEL questionnaire is

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generally not practical for routine clinical practice but is adequate for clinical research
trials.

5. Ocular Surface Disease QoL Questionnaire

The Ocular Surface Disease (OSD) QoL focuses on QoL and not patient

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symptoms.95 The Dry Eye–Related Quality-of-Life Score (DEQS) was developed in
Japan.11 It is a 15-item questionnaire that contains an Overall Summary scale as well as

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two subscales (Impact on Daily Life and Bothersome Ocular Symptoms). The DEQS is
appropriate for use in everyday clinical practice.

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C. Comparison of Questionnaires

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Comparison studies have been conducted to evaluate differences between the
questionnaires to ascertain their reproducibility as well and their strengths and
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weaknesses. One study that compared the discriminative properties of the IDEEL, SF36,
and EQ-5D reported that significant differences between severity levels were found with
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most SF-36 scales, all EQ-5D scales, and all IDEEL scales, except for Treatment
Satisfaction.12 However, the IDEEL scales consistently outperformed the generic QoL
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measures, regardless of the disease severity criterion. Abetz and colleagues found that
correlations between IDEEL and DEQ were higher than between IDEEL and Short-
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Form-36 and EuroQoL-5D,94 indicating concurrent validity of these two questionnaires

focused on DED. Another study, comparing the NEI-VFQ and OSDI, found that the
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highest correlations between the two questionnaires were for: ocular pain and mental
function with regard to OSDI-symptoms; and general vision, ocular pain, mental
function, role function, and driving with regard to OSDI-function.15 The OSDI correlated
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significantly with the McMonnies questionnaire, the NEI-VFQ, the physical component
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summary score of the Short Form-12, patient perception of symptoms, and artificial tear
usage.72 The DEQS questionnaire correlates with the mental component of the Short
Form-8 and with 4 subscales (Ocular Pain, Near Vision, Distance Vision, and Mental
Health) of the NEI-VFQ-25.11
Although the described questionnaires have utility in both research and clinical
practice settings, patient symptoms cannot be assessed alone. A DED diagnosis should be

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established with tear tests (e.g., TFBUT)8 and corneal and conjunctival staining tests,
which can be used to obtain a differential diagnosis of DED and assess ocular surface
damage.8,96 Symptoms and ocular surface damage may be used as key points to make
decisions about first line therapy.97

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V. Consequences of Decreased Quality of Life in Dry Eye Syndrome
The consequences of a decreased QoL associated with DED are many and varied.11,98

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A large study in the VA hospital system found an inverse correlation between DEQ5 and
IDEEL scores relating to the ability to perform activities of daily living, emotional well-

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being, and the ability to work.99 Another study found that participants with DED were
more likely to experience problems with reading, carrying out professional work, using a
computer, watching television, driving during the day, and driving at night.98

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For some patients, the severity of the condition and its chronicity led to mood
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alterations and depression. In the United Kingdom, patients with primary Sjögren
syndrome (SS) had high scores in an evaluation of clinical depression, as well as a higher
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prevalence of depression than their counterparts without DED.100 Also, patients with
primary SS had significantly higher scores for possible clinical anxiety and for clinical
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depression compared with the age-matched group with rheumatoid arthritis.101 Both the
physical and mental well-being of the SS patients were significantly reduced compared
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with the control group. Furthermore, SS patients experienced low mood, irritability,
headache, gastrointestinal symptoms, and impaired concentration and memory more
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often than the patients with rheumatoid arthritis. Significant correlations between QoL
scores and depression and anxiety levels were found in patients with dry eye.102 These
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findings underscore the serious of the impact of DED on patients’ daily lives.
A consequence of DED that is often overlooked is its economic impact on
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patients and their caregivers. Direct resource utilization among those with DED includes
professional visits for healthcare, non-pharmacological therapies, pharmacological
treatments, and surgical procedures, with the last two aspects comprising the bulk of the
cost.103 There is a wide array of diagnosis and treatment practice patterns, but current
therapies are not always effective.

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Given the high prevalence of DED, indirect costs can be substantial. Mizuno et al
conducted a study in Japan that estimated the annual direct cost incurred by dry eye
patients, including costs for treatment, medications, and punctual plugs.104 The average
number of hospital visits made by the patients was 5.8 per year. For those who used
ophthalmic solutions, the average annual drug cost was US$323. A study that estimated

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the economic burden of DED in the U.S. found the annual cost at $783/patient with an
overall cost across the country (accounting for prevalence) at nearly $4 billion.105

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When the loss of productivity and prevalence of DED are considered, the societal
costs per year have been estimated at over $55 billion in the U.S. These data highlight the

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large economic burdens to individuals and society that are due to DED.

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VI. Conclusions
Dry eye is a multifactorial disease that can cause discomfort and a reduced quality
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of life. Several survey instruments and diagnostic tools are available to help the physician
to arrive at a differential diagnosis of the disease and to monitor the effect of therapies.
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Patient education and counseling to emphasize the need for consistent treatment are key
factors in the successful management of DED, as well as the development of new
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treatments aimed at reducing the invalidating symptoms of the disease.

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Acknowledgements
The authors would like to thank Julie Crider, PhD for editorial contributions and
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Farmigea for travel and organization support.

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Figure legends

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Figure 1. Symptoms behavior during the day is different in dry eye disease, allergy and
blepharitis.9

Figure 2. Tear break-up in a group of patients who underwent cataract surgery. A

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significant decrease was recorded at days 1, 7, and 30. Normal values were
demonstrated after 60 days.64

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Tables:

Table 1. Common Dry Eye Symptoms

• Itching

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• Burning
• Stinging
• Pain
•

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Soreness, sticky eyes
• Sensitivity to bright light / sunlight
• Feeling akin to having a grain of sand in the eye (foreign body sensation)
•

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Ocular irritation
• Blurred vision, poor vision
• Intolerance to windy conditions & air conditioned
• Intolerance to contact lenses

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• Ocular redness

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Table 2. Medical History

Ongoing Treatments or Ongoing Diseases or

Concerning DED
Medications Medical Conditions

Date of onset Topical Extra-ocular dryness

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Chronicity Preservatives Joint pain

Before the onset Systemic Endocrinal pathologies

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Thyroid disorders
Infection Antidepressants
(hyper or hypo)

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Other treatments with anti-
Trauma Diabetes
muscarinic properties

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Acne treatments such as
After a topical treatment Intestinal disorders
retinoids

Special geographic
locations or activities
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Antimitotic drugs HIV infections
causing relapse
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Seasonal Bone marrow grafts HCV infections
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Addictive drugs
HTLV infections
(opioids, cannabis)
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HIV-related treatments Menopause

Hormone replacement
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Surgery
therapy

Progesterone
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Thyroxin
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Table 3. Steps for Building and Validating a Questionnaire (Falissard et al., 2003; Sakane et al.,
2013)

1. Based on
a. Good theoretical knowledge of the problem
b. Good practical knowledge of every-day life
2. List of ALL potential items

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a. Discussion with patients & some (few) experts
3. Selection of final items for the questionnaire
a. Panel of 10 to 50 experts
i. Delphi method

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ii. Panel of experts method (time consuming +++)
4. Defining the scores of each item
a. 0 / + / ++ / +++ equivalent to 0-1-2-3

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b. Validation
5. Pilot study with some patients - Cognitive Debriefing Test
a. Participants’ general impressions
b. Comprehensiveness of the questionnaire

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c. Clarity of the instructions and the items/response choice
d. Readability of the format and layout
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e. Time required to complete the questionnaire
6. Preliminary Validation Study (Preliminary Construct Validity)
a. Validation of the scoring system
7. Validation study with a sufficient amount of patients
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a. Concordance & correlation with hard data
i. Example: a questionnaire on severity of symptoms should provide
answers correlated with the REAL severity of the disease
1. Definition of severity? Validation of previous scales?
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b. Concordance & correlation between answers

i. Must be high
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1. But not overly to (what do you mean here?)(equivalent to a

single question)
c. Metrologic qualities
i. Reproducibility (test-retest, inter-judge)
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ii. Reliability
iii. Internal consistency
iv. Sensibility to changes
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Table 4. Questionnaires Used in the Diagnosis and Treatment of Dry Eye Disease. (From Ridder, 2011 and
DEWS Epidemiology Report, 2007)
Items Relating to
Items Relating to Visual Activities of Daily
Instrument Questions Potential Use
Function Living (ADL) and
Quality of Life (QoL)
Ocular Surface 12 3 items related to 1) eyes 4 items on how eye Measures the severity of dry
Disease that are sensitive to light; problems limit 1) eye disease; end points in

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Index (OSDI): 2) blurred vision; 3) poor reading, 2) driving at clinical trials, symptoms,
Schiffman RM et vision. night, 3) working functional problems and
al.72 at computer or bank environmental triggers
machine (ATM), 4) queried for the past week

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watching
television.
Impact of Dry Eye 57 2 items on how “blurry 9 items on how dry eye Daily clinical practice and
on 3 Modules vision” or “sensitivity to (DE) limits ADLs; 12 research setting

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Everyday Life treatment light, items on how DE
(IDEEL): satisfaction glare, and/or wind” affects feelings; 5 items
Rajagopalan K et bothers the patient. on how DE affects
al.12 work.

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Texas Eye 42 1 item: “Eyes bother Daily clinical practice
Research & you so much that you
Technology
Center Dry Eye
Questionnaire
AN had to stop whatever
you were doing…”

(TERTC-DEQ):
Narayanan S et
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al.73
Eye Allergy 35 questions 1 item: Generally, on Studies of ocular allergy
Patient Impact 4 Sections the days you performed
Questionnaire tasks at work, school,
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(EAPIQ): and home with eye

Alexander M et allergy symptoms, how
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al.74 effective were you?

7 items: how eye
symptoms affect
ADLs; 8
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items on how eye

symptoms
affect feelings
National Eye 25 1 item on “how much Useful tool for group-level
Institute pain or comparisons of vision-
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Visual discomfort in or around targeted, health-related

Functioning your QOL in clinical
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Questionnaire eyes keeps you from research; not influenced by

(NEI VFQ)- doing severity of underlying eye
25:Mangione CM what you’d like to be disease, suggesting use for
et al.75 doing?” multiple eye conditions.
Dry Eye 21 4 questions related to Epidemiologic and clinical
Questionnaire: “changeable, blurry studies
Begley CG et vision.”
al.17,76
Dry Eye 19 1 item on photophobia: Screening
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